ABSTRACT ? Overall Nearly 600,000 new HIV infections occur yearly in adolescents/young adults (ages 15-24 years), the only population in which HIV infections continue to rise. The end of the HIV/AIDS epidemic will be achievable only when an effective vaccine regimen can elicit long-term protective immunity in preadolescence, prior to sexual debut. Yet, even the most promising HIV envelope (Env) vaccine platforms have failed to induce highly- protective immunity in adults in preclinical and clinical studies. Interestingly, recent studies indicate that durable, polyfunctional, and broad neutralizing antibody (bnAb) responses following HIV infection occur more frequently and are equal or more potent in infants compared to that of adults. Yet, there remains a gap in our understanding of the immunologic mechanisms associated with the rapid induction of HIV bnAb and effector antibody functions within the infant immune landscape. The overall goal of this HIVRAD renewal is to harness the unique qualities of the early life immune system for vaccine elicitation of protective HIV immunity. This work builds on our current HIVRAD Program focusing on the development of HIV Env vaccine regimens for prevention of infant HIV acquisition. We defined the optimal vaccine intervals, adjuvants, and doses to achieve maximal immunogenicity in the infant immune system, and determined that concurrent passive bnAb-active HIV Env immunization does not impair vaccine-elicited immune responses. In this renewal HIVRAD Program, we hypothesize that HIV Env vaccine platforms administered in early life and boosted in preadolescence will achieve more durable, broad, and polyfunctional immune responses and be more efficacious at prevention of sexual transmission than initiation of immunization in preadolescence. We will compare vaccine responses to two of the most promising HIV Env vaccine candidates, bnAb germline-targeting SOSIP trimers (Project 1) and lipid nanoparticle mRNA vaccines (Project 2) initiated in infancy with boosting throughout childhood to that of initiation of vaccination in preadolescence in the rhesus model (Nonhuman Primate (NHP) Core), and test their efficacy against intrarectal homologous and heterologous SHIV challenge in adolescence. We will apply systems immunology to define the immunologic, transcriptomic, and microbiologic signatures associated with the HIV Env vaccine antibody function and induction of bnAb precursors (Integrated Systems Immunology Core (ISIC)). The Administrative Core provides the full range of support for scientific, fiscal, and other programmatic management and oversight. By leveraging the extended window for maturation of vaccine-induced responses and defining the mechanistic advantages of early life immunization for effective anti-HIV responses, this Program will inform the target population and design of an HIV Env vaccine that will provide life-long protection.